Renewal of Grant NS 09931-07 is requested for five years to continue experimental and theoretical studies on the selective ion permeation through peptide channels and carriers across lipid bilayer membranes to provide a foundation for understanding, at a molecular level, the ion selectivity and permeation mechanisms of nerve. For channels, we propose to exploit our recent demonstration for the gramicidin channel of heretofore unsuspected selectivity among monovalent cations, associated with multiple occupancy of four specific ion binding sites, which is manifested in concentration dependent permeability ratios, saturation, and block closely analogous to similar phenomena in the Na ion and K ion channels of nerve. These studies should extend the basis laid by Hille and Armstrong for using cations as "probes" of the structure of the Na ion and K ion channels of nerve, extending this to the selectivity filters as well as the binding sites. For carriers, we propose to apply the well advanced theories to the analysis of structure-function relationship in a series of synthetic cyclic, purely peptide, carriers of cations, which we have discovered act similarly to the conventional macrocyclic antibiotics. These offer the possibility to understand the functional significance of different amino acid side chains, which should be pertinent to the selectivity of membrane proteins. We will apply a judicious blend of theoretical development and experimental characterization to reconstituted membrane systems of known chemical composition and ultimately of developing a truly molecular understanding of the ion selectivity and permeation processes of the Na ion and K ion channels of nerve.